The Selective Protection and Deprotection of Ambident Nucleophiles with Parent and Substituted Triarylmethyls

The last few years have seen a tremendous improvement in the methods used to protect hydroxy groups with trityls. However, there is limited work on the selective protection and deprotection of ambident nucleophiles (e.g. amines, alcohols and sulfurs) with trityls and p-methoxy substituted trityls. Methoxysubstituted trityl functions have been used as N-protecting groups in pro-drugs, designed to release the amino function selectively in tumor cells because of the purported lower pH of these cells relative to normal cells. The application of 4,4’-dimethoxytrityl to the protection of the 5’-hydroxy groups in nucleotides was a breakthrough that led to the rational synthesis of oligonucleotides. The diand trinucleotides bearing the N-trityl-p-aminophenyl group were isolated by solvent extraction, and the protecting group was removed by mild oxidative hydrolysis. The resulting tetranucleotide (pTpTpTpT) was finally purified by ion-exchange chromatography. ∗Corresponding author